Anxiety is a pathological counterpart of fear and is often accompanied by disturbances of mood, thinking, behavior, and physiology. Whereas fear is typically triggered by a perception of a threat in the environment, anxiety disorders typically involve a fearfulness which is either unprovoked by an environmental threat or highly disproportionate to an environmental threat.
Anxiety disorders are among the most common mental disorders and can greatly limit the quality of life. In an anxiety disorder, an extreme or pathological anxiety is generally the principal disturbance of mood or emotional tone. Such disorders include, but are not limited to, panic disorder (with and without a history of agoraphobia), agoraphobia (with and without a history of panic disorder), generalized anxiety disorder, specific phobia, social phobia, obsessive-compulsive disorder, acute stress disorder, and post-traumatic stress disorder. In addition, there are adjustment disorders with anxious features, anxiety disorders due to general medical conditions, substance-induced anxiety disorders, and the residual category of anxiety disorder not otherwise specified (See DSM-IV).
Cognitive-behavioral therapies can be beneficial for many patients with anxiety disorders (Chambless et al., 1998). Benzodiazepines, antidepressants, selective serotonin reuptake inhibitors and the novel compound buspirone (Lydiard et al., 1996) have been used with some success in the treatment of anxiety and anxiety disorders. Treatments combining psychotherapy and pharmacotherapy are also beneficial (March et al., 1997; American Psychiatric Association, 1998). One limitation of such psychotherapeutic treatments has been their cost and the reluctance of patients to enter such treatment. Many of the pharmaceutical treatments rely upon drugs, most particularly the important class of benzodiazepines, which have some addiction or abuse potential. As the anti-anxiety pharmacopeia is relatively bare, there is a need for additional therapeutic agents to treat anxiety and anxiety disorders.
Anxiety is one of the few mental disorders for which animal models are available. Researchers can reproduce symptoms of human anxiety in test animals by manipulating physical or psychosocial stressors. These animal models provide a means for screening compounds for anti-anxiety activity. In light of increasing awareness of numerous neurochemical alterations in anxiety disorders, many new classes of drugs are likely to be developed through such screening.
The psychoactive constituent of Cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), produces in humans subjective emotional responses mediated by CB1 cannabinoid receptors, suggesting that endogenous cannabinoids may contribute to the regulation of mood and emotions. But the variable effects of Δ9-THC—which, depending on dosage, range from relaxation and euphoria to anxiety and panic attacks—obscure the interpretation of these results and limit the therapeutic potential of direct-acting cannabinoid agonists.
Anandamide, the naturally occurring amide of arachidonic acid with ethanolamine, meets all key criteria of an endogenous cannabinoid substance (Devane, W. A. et al. Science, 258, 1946-1949 (1992)): it is released upon demand by stimulated neurons (Di Marzo, V. et al., Nature, 372, 686-691 (1994); Giuffrida, A. et al., Nat. Neurosci., 2, 358-363 (1999)); it activates cannabinoid receptors with high affinity (Devane, W. A. et al. Science, 258, 1946-1949 (1992)) and it is rapidly eliminated through a two-step process consisting of carrier-mediated transport followed by intracellular hydrolysis (Di Marzo, V. et al., Nature, 372, 686-691 (1994); Beltramo, M. et al., FEBS Lett., 403, 263-267 (1997)). Anandamide hydrolysis is catalyzed by the enzyme fatty acid amide hydrolase (FAAH), a membrane-bound serine hydrolase (Cravatt, B. F. et al., Nature, 384, 83-87 (1996); Patricelli, M. P. et al., Biochemistry, 38, 9804-9812 (1999)) (WO 98/20119) (U.S. Pat. No. 6,271,015) that also cleaves other bioactive fatty ethanolamides, such as oleoylethanolamide (cis-9-octadecenamide)) (Rodriguez de Fonseca, F. et al. Nature, 414, 209-212 (2001)) and palmitoylethanolamide (Calignano, A. et al., Nature, 394, 277-281 (1998)). Mutant mice lacking the gene encoding for FAAH cannot metabolize anandamide (Cravatt, B. F. et al., Proc. Natl. Acad. Sci. U.S.A., 98, 9371-9376 (2001)) and, though fertile and generally normal, show signs of enhanced anandamide activity at cannabinoid receptors, such as reduced pain sensation (Cravatt, B. F. et al., Proc. Natl. Acad. Sci. U.S.A., 98, 9371-9376 (2001)). This suggests the possibility that drugs targeting FAAH may heighten the tonic actions of anandamide, while possibly avoiding the multiple, often unwanted effects produced by Δ9-THC and other direct-acting cannabinoid agonists (Hall, W., et al., Lancet, 352, 1611-1616 (1998); Chaperon, F., et al., Crit. Rev. Neurobiol., 13, 243-281 (1999)).
Most current inhibitors of the FAAH enzyme lack the target selectivity and biological availability needed for in vivo studies (Koutek, B. et al., J. Biol. Chem., 269, 22937-22940 (1994); De Petrocellis, L. et al., Biochem. Biophys. Res. Commun., 231, 82-88 (1997); Deutsch, D. G. et al., Biochem. Biophys. Res. Commun., 231, 217-221 (1997); Beltramo, M. et al., FEBS Lett., 403:263-267 (1997)), while newer compounds, though promising, have not yet been characterized (Boger, D. L. et al. Proc. Natl. Acad. Sci. U.S.A., 97, 5044-5049 (2000)). Thus, the therapeutic potential of FAAH inhibition with respect to the endogenous cannabinoid system activity remains essentially unexplored.
The present invention expands the pharmacopeia for the inhibition of FAAH and the treatment of anxiety and other conditions by providing a new class of FAAH inhibitors and new methods for treating anxiety and anxiety disorders or conditions by administering FAAH inhibitors.